Process for the preparation of tiotropium bromide

ABSTRACT

The invention is directed to improved processes for preparing Tiotropium bromide.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/403,984, filed Mar. 13, 2009, now U.S. Patent No. 7,662,963, which isa divisional of U.S. patent application Ser. No 11/827,443, filed Jul,10, 2007, now abandoned, which, in turn, claims the benefit of thefiling date of U.S. Provisional Patent Application No. 60/830,231 filedJul, 10, 2006; U.S. Provisional Patent Application No, 60/835,201, filedAug. 3, 2006; U.S. Provisional Application No. 60/835,200, filed Aug. 3,2006; and U.S. Provisional Application No. 60/836,037, filed Aug. 7,2006, the disclosures of which are hereby incorporated herein byreference. This application is also related to U.S. patent applicationSer. No. 11/643,013, filed Dec. 19, 2006, now abandoned.

FIELD OF THE INVENTION

The invention is directed to improved processes for preparing Tiotropiumbromide.

BACKGROUND

Tiotropium bromide, (1α, 2β, 4β, 5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0]nonanebromide or 6β, 7β-epoxy-3β-hydroxy-8-methyl-1αH, 5αH-tropanium bromide,di-2-thienylglycolate, has the following chemical structure:

It is an anticholinergic drug with specificity for muscarinic receptors.As a bronchodilator it provides therapeutic benefit in the treatment ofasthma or chronic obstructive pulmonary disease (COPD). This activepharmaceutical ingredient is administered by inhalation, and isavailable commercially as SPIRIVA® HandiHaler®.

Tiotropium bromide was first disclosed in U.S. Pat. No. 5,610,163 whereit was synthesized via N-demethyl tiotropium of formula III,

which was obtained by a reaction of methyl di(2-thienyl)glycolate offormula I and Scopine of formula II using sodium metal in melt or sodiummethoxide in melt. Because of the dangerous reaction conditions, thismethod is not suitable for industrial scale preparation. Thequaternization of N-demethyl-tiotropium is then carried out in a mixtureof acetonitrile and methylene chloride using methyl bromide as aquaternizing agent. The process is illustrated in the following scheme:

The product was then crystallized from a mixture of acetone andmethanol.

Also described in the prior art is the preparation of Scopine HCl, whichwas first disclosed in GB 1469781, wherein it was prepared by reductionof scopolamine using sodium borohydride, followed by addition of HCl tothe reaction mixture, a process illustrated by the following scheme:

This salt of scopine can be used as a precursor for scopine base,however a process to remove inorganic salts from the desired product isnot reported.

U.S. Pat. Nos. 6,486,321 and 6,506,900 disclose a synthesis ofTiotropium and analogues via tropenol derivatives by introducing anadditional epoxidation step, as described by the following scheme.

U.S. Pat. No. 6,747,154, refers to formal approaches by stating “Theseprocesses known in the art may also be used to prepare the compounds offormula 1.

However, these methods of synthesis are more complex proceduresinvolving a number of synthetic steps.” Therefore a different syntheticapproach was developed, where the coupling is carried out using scopinemethobromide rather than scopine, but details, including the yield, ofthis coupling reaction are not reported.

United States Patent Publication No 2006/0047120 describes yet anotherapproach, coupling scopine methobromide with trimethylsilyl-protectedsodium dithienyl glycolate which is obtained in situ.

This application, provides that this approach was developed to improvethe prior art synthesis for Tiotropium bromide.

Hence, an improved process to prepare Tiotropium bromide is needed.

SUMMARY OF THE INVENTION

In one embodiment, the present invention encompasses scopine salt offormula II-s:

containing about 0.5% to about 40% by weight of salts; wherein X is Br,Cl, SO₄, MeCOO, PO₄, MeSO₃, tartrate, fumarate, citrate, maleate,succinate, p-toluene sulphonate or amidosulphonate.

In another embodiment, the present invention encompasses a process toconvert scopine salt of formula II-s containing about 0.5% to about 40%by weight of salts to Tiotropium bromide of formula IV.

In yet another embodiment, the present invention encompasses thepreparation of N-demethyl-tiotropium of formula III,

comprising combining methyl-di-(2-thienyl)-glycolate of formula I,

a weak inorganic base, a polar organic solvent and scopine salt offormula II-s

containing about 0.5% to about 40% by weight of salts to obtain amixture, and heating the mixture.

In one embodiment, the present invention encompasses a process for thepreparation of Tiotropium bromide comprising a) combiningmethyl-di-(2-thienyl)-glycolate of formula I,

a weak base, a polar organic solvent, and scopine salt of formula II-scontaining about 0.5% to about 40% by weight of salt to obtain amixture; b) heating the mixture providing N-demethyl-tiotropium offormula III; c) recovering the N-demethyl-tiotropium of formula III; d)combining N-demethyl-tiotropium of formula III with methylbromide (MeBr)and an organic solvent to yield Tiotropium bromide.

In another embodiment, the present invention encompasses a process toprepare Tiotropium bromide, by preparing N-demethyl-tiotropium offormula III by the process of the present invention, and furtherconverting it to Tiotropium bromide.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “room temperature” refers to a temperatureranging from about 20° C. to about 26° C.

The present application discloses a novel approach to the synthesis ofTiotropium bromide, in particular from a Scopine hydrohalide of formulaII-s, and even more specifically, from scopine HBr of the formula

that contains a low level of salts, as compared to the process disclosedin GB '781, where the obtained scopine HCl contained a high level ofmore than 60% by weight of inorganic salts. These salts are insoluble inwater, and thus cannot be removed by a simple washing operation.

Typically, scopine hydrohalide containing low level of salts refers toscopine salt with less than 40% by weight of salts. Typically, themeasurement of the salts content is done by sulfuric ashes, asexemplified in example 1.

Moreover, the inventors of this application have found that the purityof the scopine salt affects the purity and the yield ofN-demethyl-tiotropium of formula III, a key intermediate in thesynthesis of Tiotropium bromide.

For example, without restricting the invention, using pure scopine saltleads to higher yield and purity, as will be further demonstrated.

The present invention encompasses scopine salt of formula II-s

containing about 0.5% to about 40% by weight of salts; wherein X is Br,Cl, SO₄, MeCOO, PO₄, MeSO₃, tartrate, fumarate, citrate, maleate,succinate, p-toluene sulphonate or amidosulphonate.

Preferably, scopine salt of formula II-s contains about 0.5% to about20% by weight of salts, more preferably of about 0.5% to about 15% byweight, even more preferably of about 0.5% to about 5% by weight, andmost preferably of about 0.5% to about 1% by weight. As mentionedbefore, the content of the salts can be determined by sulfuric ashes.

Preferably, the scopine salt is selected from a group consisting of HBr,HCl, H₂SO₄, CH₃COOH, H₃PO₄, MeSO₃H, tartrate, fumarate, citrate,maleate, succinate, maliate, p-toluenesulphonate, and amidosulphonate.More, preferably, the salt is HBr.

The above scopine salt of formula II-s is obtained by filtration of thereaction mixture prior to the addition of acid. The process comprises:a) filtering solids from the reaction mixture containing scopine baseand insoluble inorganic salts, such as borate salts, to produce afiltrate; b) washing the solids with a polar organic solvent; c) addingwater to the filtrate to precipitate insoluble inorganic salts; d)filtering the filtrate to remove any precipitated salts; e) washing theinorganic salts with a polar organic solvent; and f) adding an acid anda polar organic solvent to the filtrate to obtain the scopine salt offormula II-s.

The addition of water in the above process causes the remaininginsoluble salts to precipitate. Preferably, after the addition of waterthe filtrate is stirred for about 0.5 hour to about 2 hours, morepreferably for about 1 to about 1.5 hours.

Typically, the addition of water results in a precipitate formation andthus a suspension. The suspension is concentrated under vacuum, toremove water, thus increasing the yield. Preferably, the suspension isconcentrated at a temperature of no more than 55° C., more preferably ofabout 25° C. to about 55° C., most preferably of about 30° C. to about35° C.

After the suspension is concentrated, it is filtered, and washed twicewith a polar organic solvent. Preferably, the polar organic solvent isselected from a group consisting of C₁₋₆ alcohol, C₄₋₈ ether, C₃₋₁₀ketone, C₂₋₄ nitrile, and mixtures thereof. Preferably, the C₁₋₆ alcoholis C₁₋₄ alcohol, more preferably C₁₋₃ alcohol. Preferably, the C₁₋₃alcohol is methanol, ethanol or isopropanol. Moreover, absolute ethanolmay be used. A preferred C₄₋₈ ether is C₄₋₆ ether, more preferablyC₄₋₅ether. A preferred C₄₋₅ ether is either tetrahydrofuran or 1,4-dioxane.Preferably, the C₃₋₁₀ ketone is C₂₋₃ ketone. Preferably, the C₂₋₃ketones acetone. A preferred C₂₋₄ nitrile is C₁₋₂ nitrile. Preferably,the C₁₋₂ nitrile is acetonitrile. Most preferably, the solvent isethanol.

Preferably, the acid is HBr.

The obtained scopine salt of formula II-s is then converted toTiotropium bromide of formula IV. The conversion will be illustratedbelow.

The novel approach, also comprises a process for the preparation ofTiotropium bromide comprising: a) combiningmethyl-di-(2-thienyl)-glycolate of formula I,

a weak inorganic base, a polar organic solvent, and scopine salt offormula II-s containing about 0.5% to about 40% by weight of salt toobtain a mixture; b) heating the mixture providing N-demethyl-tiotropiumof formula III; c) recovering the N-demethyl-tiotropium of formula III;d) combining N-demethyl-tiotropium of formula III with methylbromide(MeBr) and an organic solvent to yield Tiotropium bromide.

The process is illustrated by the following scheme:

wherein X is Br, Cl, SO₄, MeCOO, PO₄, MeSO₃, tartrate, fumarate,citrate, maleate, succinate, p-toluene sulphonate or amidosulphonate.

The glycolate of formula I may be prepared by combining 2-bromo-tiopheneof the following formula,

Mg, and an ethereal solvent; combining with dimethyloxalate of thefollowing formula

and quenching.

Combining 2-bromo-thiophene, Mg, and an ethereal solvent provides aGrignard reagent that can be prepared, for example, according to theprocess disclosed in Nyberg, K. Acta Chemica Scandinavica, 24, 1970,1590-1596.

Methyl di-(2-thienyl)glycolate of formula I may be purified bycrystallization from a mixture of ethanol and heptane, absolute ethanoland heptane, isopropanol and heptane, and from toluene and heptane.

N-demethyl-tiotropium of formula III

is prepared under conditions, which are not dangerous, are suitable forindustrial scale preparation, and which provide a satisfactory yield.Moreover, the use of scopine salt instead of scopine base, and applyingmild conditions in the preparation of N-demethyl-tiotropium of formulaIII, decrease significantly the conversion of scopine to scopoline, aside product that occurs in basic media, as illustrated in the followingscheme:

The preparation of N-demethyl-tiotropium of formula III,

comprises combining methyl-di-(2-thienyl)-glycolate of formula I,

a weak inorganic base, a polar organic solvent, and scopine salt offormula II-s, containing about 0.5% to about 40% by weight of salts toobtain a mixture, and heating the mixture.

Initially, scopine salt of formula II-s is suspended in a polar organicsolvent. Preferably, the salt is an HBr salt. The polar organic solventis selected from a group consisting of amides, sulfoxides, sulfones,aromatic hydrocarbons, nitriles, and mixtures thereof. Preferably, thepolar organic solvent is selected from the group consisting of C₁-C₄amide, C₂-C₄ sulfoxide, C₂-C₄ sulfones, C₇-C₈ aromatic hydrocarbon, andC₂-C₄ nitrile. A preferred C₁-C₄ amide is dimethylformamide,N-methyl-2-pyrrolidone, or dimethylacetamide. A preferred C₂-C₄sulfoxide is dimethylsulfoxide. Preferably, the C₂-C₄ sulfone issulfolane. Preferably, the C₂-C₄ nitrile is acetonitrile. Preferably,the C₇-C₈ aromatic hydrocarbon is toluene. More preferably, the polarorganic solvent is dimethylformamide.

Then, the weak inorganic base is added to the suspension providing a newsuspension. Typically, an anhydrous weak inorganic base, i.e. having<0.5% of water by weight, is used in such reactions to obtain the freebase form of scopine. Preferably, the weak inorganic base has a pKa ofabout 8 to about 12, even more preferably of about 9 to about 10.Preferably, the weak inorganic base is selected from a group consistingof: K₂CO₃, NaHCO₃, Na₂CO₃, Li₂CO₃, Cs₂CO₃, t-ButOK, and t-ButOLi. Morepreferably, the weak inorganic base is K₂CO₃.

After the addition of the base, a mixture ofMethyl-di-(2-thienyl)-glycolate of formula I and another portion of theweak inorganic base are added to the new suspension, providing themixture.

Methyl-di-(2-thienyl)-glycolate of formula I can be added as solid or insolution. Preferably, methyl-di-(2-thienyl)-glycolate of formula I is insolution in the polar organic solvent.

Preferably, the weak inorganic base is present in the mixture in anamount of about 0.45 to about 2.5, more preferably, of about 2 to about2.5 mole equivalent per mole equivalent of scopine salt of formula II-s.The weak inorganic base is added in two portions to preventdecomposition of scopine and to provide favorable reaction conditions.

Preferably, the mixture of the weak inorganic base andmethyl-di-(2-thienyl)-glycolate of formula I are added at a temperatureof about 25° C. to about 65° C., more preferably at about 60° C. toabout 65° C.

Typically, the said mixture is heated in order to provideN-demethyl-tiotropium of formula III. Preferably, the said mixture isheated to a temperature of below 70° C., more preferably, of about 25°C. to about 65° C., even more preferably of about 60° C. to about 65°C., and most preferably of about 63° C. to about 65° C. Preferably,heating is done for about 17 to about 24 hours, more preferably forabout 18 to about 20 hours.

Preferably, heating is done under reduced pressure. Usually, the term“reduced pressure” refers to a pressure of about 70 to about 100millibar.

Usually, such reactions are done under inert conditions, such as underan atmosphere of nitrogen. Inert conditions are provided by bubbling aninert gas, such as nitrogen and/or argon, during the reaction, through asecond inlet. Preferably, nitrogen is bubbled in a rate of about 1.8 toabout 2.6 L/min, more preferably, of about 2.0 to about 2.4 L/min, andeven more preferably of about 2.2 to about 2.4 L/min.

The heating under reduced pressure, while bubbling nitrogen from asecond inlet, assists in evaporating methanol, which is formed duringthe reaction, hence, shifting the reaction towards the formation of theproduct.

N-demethyl-tiotropium of formula III may be recovered by cooling themixture; adding an acid to the cooled mixture providing a two phasesystem comprising of an organic and aqueous phases; extracting theaqueous phase with an organic solvent; adding a base to the aqueousphase to precipitate N-demethyl-tiotropium of formula III; filtering theprecipitate N-demethyl-tiotropium of formula III; washing and drying theN-demethyl-tiotropium. Preferably, the acid is HBr.

Preferably, the heated mixture is cooled to a temperature of about 10°C. to about −10° C., more preferably to about 5° C. to about 0° C.

Preferably, the addition of the acid provides a pH of about 2 to about3.5. Preferably, the organic solvent is toluene.

Preferably, the weak inorganic base is added at a temperature of about0° C. to about 5° C. Preferably, the weak inorganic base is selectedfrom a group consisting of: K2CO3, NaHCO3, Na2CO3, Li2CO3, Cs2CO3,t-ButOK, and t-ButOLi. Preferably, the weak inorganic base is K2CO3.

Preferably, the precipitate is washed with water to obtain pH of about7.

Optionally, scopine base may be used instead of scopine salt. Whenscopine base is used, typically, a smaller amount of the weak inorganicbase is required. Preferably, about 1 to 1.5 mole equivalent of weakinorganic base per mole equivalent of scopine base may be used.

The obtained N-demethyl-tiotropium of formula III may then be convertedto Tiotropium bromide. The conversion can be done, for example, by theprocess disclosed in U.S. Pat. No. 5,610,163 or by the process of thepresent invention described below.

The conversion of N-demethyl-tiotropium of formula III to Tiotropiumbromide can be done by reacting N-demethyl-tiotropium of formula IIIwith methyl bromide in an organic solvent.

Initially, N-demethyl-tiotropium of formula III and the organic solventare combined to obtain a suspension.

Preferably, the organic solvent is selected from a group consisting ofC₂₋₄ nitrile, C₄₋₈ linear or cyclic ether, mixtures of C₂₋₄ nitrile andC₄₋₈ linear or cyclic ether, mixtures of C₇₋₈ aromatic hydrocarbon andC₂₋₄ nitrile, and mixtures of C₂₋₄ nitrile and C₃₋₁₀ ketone. Preferably,the C₂₋₄ nitrile is acetonitrile. A preferred C₄₋₈ linear or cyclicether is tetrahydrofuran. Preferably, a mixture of C₂₋₄ nitrile and C₄₋₈linear or cyclic ether is that of acetonitrile and tetrahydrofuran. Apreferred mixture of C₇₋₈ aromatic hydrocarbon and C₂₋₄ nitrile is thatof toluene and acetonitrile. Preferably, a mixture of C₂₋₄ nitrile andC₃₋₁₀ ketone is that of acetone and acetonitrile. Most preferably, thesolvent is acetonitrile.

Methyl bromide is then added to the suspension to provide a mixture.Methyl bromide can be used as a gas or in solution. Preferably, methylbromide is used in solution, where the solvent is an organic solventthat is described above.

The mixture is the maintained at a temperature of about 20° C. to about40° C. Preferably, the mixture is the maintained at a temperature ofabout 20° C. to about 25° C.

Typically, the mixture is maintained to allow the formation ofTiotropium bromide. Preferably, the mixture is maintained for about 12to about 64 hours, more preferably for about 18 to about 22 hours.

Tiotropium bromide may then be recovered by any method known in the art,such as filtering and drying. Tiotropium bromide may then be purified bycrystallization from ethanol. Preferably, crude Tiotropium bromide isdissolved in ethanol. More preferably, the ethanol is absolute ethanol.Preferably, the dissolution is done by heating to a temperature of about75 to about 78° C. Typically, after dissolution, the solution is cooledto a temperature of about to about 25° C. to induce precipitation ofTiotropium bromide. Preferably, cooling is done over a period of about 6to about 8 hours.

The precipitate is recovered from the suspension by filtration, washedwith absolute ethanol, and dried.

Having described the invention with reference to certain preferredembodiments, other embodiments will become apparent to one skilled inthe art from consideration of the specification. The invention isfurther defined by reference to the following examples describing indetail the preparation of the composition and methods of use of theinvention. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the scope of the invention.

EXAMPLES

Sulfuric ashes methodology for determining the level of salts in scopineHBr:

1 g (exactly weighed) of scopine HBr was placed in a platinum meltingpot. Sulphuric acid 96% was added, and then placed in an oven at 600° C.until a constant weight was achieved. The melting pot, with theinorganic residue inside, was weighed to afford the percent of inorganicsalts present in the original material.

Example 1 Comparative Example Preparation of Scopine HydrochlorideAccording to GB '781

10.0 g (22.84 mmol) of scopolamine hydrobromide trihydrate was suspendedin 100 mL of absolute ethanol, and cooled to about 0° C. Sodiumborohydride (4.0 g, 105.7 mmol) was then added portion-wise whilemaintaining the temperature at a maximum of 30° C.4.8 mL of water wasthen added to the reaction mixture. After 3.5 hours, the reaction wascompleted and 50 mL of diethyl ether was then added. The reaction wasthen cooled to 0° C., and acidified with 2M hydrochloric acid in diethylether to a pH of about 2. The suspension was stirred at room temperaturefor 30 minutes and then filtered on GochP3. The white solid was dried at45° C. under vacuum for 4 hours, yielding 9 g of product containing 79%of salts determined by sulphuric ashes.

Example 2 Preparation of Methyl di-(2-thienyl)glycolate

1050 mL of tetrahydrofuran was loaded in a 2 L round bottomed flask.22.6 g (0.93 mol) of magnesium turnings were then added, and the mixturewas kept at 35° C., while catalytic bromoethane (200 mg, 1.84 mmol) wasloaded. 150 g (0.92 mol) of 2-bromothiophene was added dropwise, andafter about 15% (13 ml) of reagent was exothermicity was observed. Thetemperature was maintained at a maximum of 50-55° C., and the remaining2-bromothiophene was then added. At the end of the addition, thereaction mixture was heated to 65° C. for 1.5 hours to 2 hours, and thencooled to 25° C.

The Grignard solution thus formed was added drop-wise, in about 2.5hours to 3 hours, into a solution of dimethyl oxalate (54.3 g, 0.46 mol)dissolved in 300 mL of tetrahydrofuran, while maintaining thetemperature at maximum 5-10° C. via cooling bath.

The solution was kept under stirring for 0.5 hours to 1.0 hours at 5-10°C., and then saturated ammonium chloride (1400 mL of a mixture of 650 gsolid ammonium chloride and 2000 mL water) was added at 0° C., whilemonitoring the temperature (maximum 15-20° C.). Then, 150 mL of waterand 625 mL of toluene were added. The separated organic phase was washedwith water (900 mL), and then with brine (900 mL).

To the organic phase 7.5 g of charcoal was added, and the mixture washeated to 40° C. and stirred at this temperature for one hour.

The mixture was then filtered on decalite pad, and washed three timeswith toluene (3×150 mL)

This solution was concentrated at 50-55° C. under vacuum (about 30 mmHg)to 270 mL, heated to 65° C., and then 720 mL n-heptane was addeddrop-wise over 2.5 hours.

The solution was stirred for one hour at 65° C., and then cooled in 3hours to 25° C. (about 1° C./5 min). It was then left stirring at thistemperature for at least 8 hours, filtered on GochP3, and washed oncewith 150 mL n-heptane.

The creamy solid obtained was dried under vacuum at 45° C. for 7 hoursyielding 73.6 g (63% overall yield, HPLC purity 99.8 area %).

Example 3 Crystallization of Methyl di-(2-thienyl)glycolate in Ethanol96%/n-heptane

Crude methyl di-(2-thienyl)glycolate (2.0 g) was dissolved in ethanol96% (8.0 ml) at 45° C. 16.0 mL of n-heptane were then added drop-wise at45° C. in 20 minutes. The solution was maintained at 45° C. for hour,and then it was cooled to 0° C. in 1 hour, and left at this temperaturefor another hour. The solid was filtered on a sintered glass funnel andit was washed once with n-heptane (2 mL). Drying for 6 hours at 50° C.under vacuum yielded 1.4 g of methyl di-(2-thienyl)glycolate (70%)

Example 4 Crystallization of Methyl di-(2-thienyl)glycolate in AbsoluteEthanol/n-heptane

Crude methyl di-(2-thienyl)glycolate (10.0 g) was dissolved in absoluteethanol (30.0 mL) at 55° C. 80.0 mL of n-heptane was then addeddrop-wise at 55° C. in 30 minutes. The solution was maintained at 55° C.for 1 hour, and then it was cooled to room temperature over 3 hours, andleft at this temperature for 6 hours. The solid was filtered on asintered glass funnel and it was washed once with n-heptane (10.0 mL).Drying for 18 hours at 50° C. under vacuum yielded 8.0 g of Methyldi-(2-thienyl)glycolate (80%).

Example 5 Crystallization of Methyl di-(2-thienyl)glycolate inIsopropanol/n-heptane

Crude methyl di-(2-thienyl)glycolate (5.0 g) was dissolved inisopropanol (20.0 mL) at 60° C. 40.0 mL of n-heptane was then addeddrop-wise at 60° C. in 30 minutes. The solution was maintained at 45° C.for 1 hour, and then it wais cooled to 0° C. in 1 hour, and left at thistemperature for another hour. The solid was filtered on a sintered glassfunnel, and it was washed once with n-heptane (5.0 ml). Drying for 12hours at 50° C. under vacuum yielded 3.6 g of methyldi-(2-thienyl)glycolate (72%).

Example 6 Crystallization of Methyl di-(2-thienyl)glycolate inToluene/n-heptane

Crude methyl di-(2-thienyl)glycolate (250.0 g) was dissolved in toluene(500 mL) at 55° C. 1750 mL of n-heptane was then added drop-wise at 55°C. in 2.5 hours. The solution was maintained at 55° C. for 1 hour, andthen it was left to cool to room temperature over 16 hours, and thencooled to 0° C., and left at this temperature for 2 hours. The solid wasfiltered on a sintered glass funnel and it was washed twice withn-heptane (2×150 mL). Drying for 16 hours at 50° C. under vacuum yielded184.1 of methyl di-(2-thienyl)glycolate (73.6%)

Example 7 Preparation of Scopine Hydrobromide in Ethanol 96%

100 g (0.228 mol) of scopolamine hydrobromide trihydrate was suspendedin 1000 mL of ethanol 96%, and cooled to 0° C. Well ground sodiumborohydride (30.23 g, 0.80 mol) was then added portion-wise, whilemaintaining the temperature at maximum 25-30° C., gas evolution wasnoticed.

The reaction mixture was left stirring at room temperature for 16 hours,and then filtered on decalite pad, and washed twice with 100 mL ofethanol 96%. Water (19 mL) was added to the filtered solution, it wasleft stirring for 1.5 hours, and the obtained white suspension wasconcentrated under vacuum (about 30 mmHg) at maximum 55° C. to give aresidue of 300 mL. After 30 minutes at room temperature, the residue wasfiltered on GochP3, and washed twice with 50 mL of ethanol 96%.

The solution was then cooled to 0° C., and acidified with 30 mLhydrobromic acid 48% to a pH of 1. 700 mL tetrahydrofuran was addeddrop-wise, in 3 hours, to the reaction mixture at 0° C., and it wasmaintained at 0° C. for 5 hours. The white solid was then filtered onGoch P3, washed with 100 mL tetrahydrofuran, and dried at 50° C. undervacuum for 16 hours, yielding 33.2 g (64% yield, sulphuric ashes 0.7%).

Example 8 Preparation of Scopine Hydrobromide in abs.ethanol withPrecipitation in HBr 48%

5 g (11.4 mmol) of scopolamine hydrobromide trihydrate was suspended in50 mL of absolute ethanol, and cooled to 0° C. Well ground sodiumborohydride (1.73 g, 45.7 mmol) was then added portion-wise whilemaintaining the temperature at a maximum of 30° C.

4.0 ml water was then added to the reaction mixture, and then after 30minutes, the suspension was filtered on decalite pad, and washed with 30mL of absolute ethanol.

The obtained solution was concentrated under vacuum at 40° C. toresidual 15 mL and, after 2 hours at room temperature, filtered onGochP3, and washed with 4 mL of absolute ethanol.

The solution was then cooled to 0° C., and acidified with hydrobromicacid 48% in water to obtain a pH of 1.

15 mL tetrahydrofuran was then added drop-wise to the reaction mixtureat 0° C., and it was maintained at 0° C. for hours and then at roomtemperature for 2 days. The white solid was filtered on Goch P3, anddried at 50° C. under vacuum for 16 hours, yielding 1.4 g (52%). Theother 40 mL THF (“tetrahydrofuran”) added to the mother liquor at 0° C.led to obtain other 700 mg product, containing 0.72% of salts.

Example 9 Preparation of Scopine Hydrobromide in abs.ethanol (5 vol)with Precipitation in HBr 48%

10.0 g (22.84 mmol) of scopolamine hydrobromide trihydrate was suspendedin 50 mL of absolute ethanol, and cooled to 0° C. Sodium borohydride(3.46 g, 68.6 mmol) was then added portion-wise while maintaining thetemperature at a maximum of 30° C.

4.8 ml of water was then added to the reaction mixture, and after 30minutes the suspension was filtered on decalite pad, and washed with 10mL of absolute ethanol.

The solution was then cooled to 0° C., and acidified with hydrobromicacid 48% in water to obtain a pH of 1.

100 mL tetrahydrofuran was added drop-wise to the reaction mixture at 0°C., and it was maintained at 0° C. for 8 hours

The white solid was filtered on Goch P3, and dried at 50° C. undervacuum for 16 hours, yielding 12.8 g (52%), containing 0.65% of salts.

Example 10 Preparation of Scopine Hydrobromide in Ethanol withPrecipitation in HBr 48%

100 g (0.22 mol) of scopolamine hydrobromide trihydrate was suspended in1000 mL of ethanol 1 96% and cooled to 0° C. Well ground sodiumborohydride (30.23 g, 0.80 mol) was then added portion-wise maintainingthe temperature at maximum 25-30° C., gas evolution was noticed. Thereaction mixture was left stirring at room temperature for 16 hours andthen filtered on decalite pad, and washed twice with 100 mL of Ethanol96%. 19 mL water was added to the filtered solution, and it was leftstirring for 1.5 hours. The obtained white suspension was concentratedunder vacuum (about 30 mmHg) at maximum 55° C. to residual 300 mL and,after 30 minutes at room temperature, filtered on GochGoch P3 and washedtwice with 50 mL of Ethanol 96%. The solution was then cooled to 0° C.and acidified with 30 mL hydrobromic acid 48% to a pH of 1. 1000 mLtetrahydrofuran was added drop-wise to the reaction mixture at 0° C. in3 hours and maintained at 0° C. for 4-5 hours. The white solid was thenfiltered on Goch P3, washed with 100 mL tetrahydrofuran and dried at 50°C. under vacuum for 16 hours, yielding 45.9 g (85.6% yield, sulphuricashes 12.7%).

Example 11 Preparation of N-Demethyl-Tiotropium

15 g (0.064 mol) of scopine hydrobromide was suspended in 165 mL ofdimethylformamide at 25° C., then 17.6 g (0.127 mol) of anhydrouspotassium carbonate were added, and the mixture was stirred at roomtemperature for about 60 minutes. 16.2 g (0.064 mol) of methyldi-(2-thienyl)glycolate were dissolved in 30 mL of dimethylformamide,and, with 4.4 g (0.032 mol) of anhydrous potassium carbonate, they wereadded to the reaction mixture at about 60-65° C. The suspension washeated to 65° C., under vacuum (70-100 mbar), and under nitrogenstripping (2.2-2.4 L/min) for 18 hours. At the end of the reaction thedistilled DMF (“dimethylformamide”) was reintroduced to the reactionmixture and another 2 volumes of DMF, for a total of 15 volumes (225mL), were added. The reaction mixture was cooled to 0° C., and acidifiedto pH 3 with about 168 mL of 2M HBr (the temperature during the additionbelow 20° C.). The obtained solution was extracted twice with mLtoluene, and the combined aqueous phases were then cooled to 0-5° C.,and basified with 8.5 g of solid potassium carbonate to a pH of 9. Afterone hour at 0° C. the solid was filtered on Goch P3, and washed fivetimes with 60 mL of water to obtain a pH of 7. The solid was dried undervacuum at 45° C. for 16 hours yielding 16.5 g (69% yield, 98.3% HPLCpurity)

Example 12 Preparation of N-Demethyl-Tiotropium with a ScopineContaining High Percent of Salts

3.0 g (0.012 mol) of scopine hydrobromide containing 69% inorganic saltswas suspended at room temperature in 27 mL of dimethylformamide, then3.4 g (0.025 mol) of anhydrous potassium carbonate were added, and themixture was stirred at room temperature for about 60 minutes. 3.1 g(0.012 mol) of methyl di-(2-thienyl)glycolate were dissolved in 9 mL ofdimethylformamide, and, with 0.85 g (0.006 mol) of anhydrous potassiumcarbonate, they were added to the reaction mixture at about 60-65° C.The suspension was heated to 65° C., under vacuum (70-100 mbar), andunder nitrogen stripping (2.2-2.4 L/min) for 18 hours. At the end of thereaction, the distilled DMF was re-added to the reaction mixture andother 2 volumes of DMF, for a total of 15 volumes (45 mL), were added.The reaction mixture was cooled to 0° C., and acidified to pH 3 with 33mL of HBr 2M (temperature during addition below 20° C.) The obtainedsolution was extracted twice with 15 mL toluene, and the combinedaqueous phases were then cooled to 0-5° C., and basified with 7.1 g ofsolid potassium carbonate to a pH of 9. After one hour at 0° C., thesolid was filtered on Goch P3, and washed five times with 30 mL of waterto obtain a pH of 7. The solid was dried under vacuum at 45° C. for 16hours yielding 1.8 g (37.5% yield, 70% HPLC purity).

Example 13 Preparation of N-Demethyl-Tiotropium from Scopine Base and aWeak Inorganic Base

5.45 g (0.023 mol) of scopine hydrobromide was suspended in 30 mL ofDCM, and then 5 g (0.036 mol) of potassium carbonate was added. Thereaction mixture was stirred at room temperature for one hour and thenfiltered on Goch P3 and washed with acetonitrile several times, (usingabout 10 ml of acetonitrile). After evaporation of the filteredsolution, 2.78 g of scopine base was obtained (77.5% yield). 3.0 g (0.02mol) of scopine base was suspended at room temperature in 27 mL ofdimethylformamide, then 2.7 g (0.02 mol) of anhydrous potassiumcarbonate was added, and the mixture was stirred at room temperature forabout 60 minutes. 4.9 g (0.02 mol) of methyl di-(2-thienyl)glycolatewere dissolved in 9 mL of dimethylformamide, and, with 1.33 g (0.0096mol) of anhydrous potassium carbonate, they were added to the reactionmixture at about 60-65° C. The suspension was heated to 65° C., undervacuum (70-100 mbar), and under nitrogen stripping (2.2-2.4 L/min) for18 hours. At the end of the reaction the distilled DMF was re-added tothe reaction mixture and other 2 volumes of DMF, for a total of 15volumes (45 mL), were added. The reaction mixture was cooled to 0° C.,and acidified to a pH of 3 with 33 mL of 2M HBr (temperature duringaddition below 20° C.). The obtained solution was extracted twice with15 mL toluene, and the combined aqueous phases were then cooled to 0-5°C., and basified with 7.1 g of solid potassium carbonate to a pH of 9.After one hour at 0° C., the solid was filtered on Goch P3, and washedfive times with 30 mL of water to obtain a pH of 7. The solid was driedunder vacuum at 45° C. for 16 hours yielding 5.1 g (69.5% yield, 98.5%HPLC purity)

Example 14 Preparation of Tiotropium Bromide

0.5 g of N-demethyl tiotropium (1.33 mmol) was suspended in a flaskunder nitrogen with 5 mL of CH₃CN. 0.525 g of CH₃Br 48% w/w solution inCH₃CN (0.00266 mol) was loaded and the suspension was left understirring at 22° C. for 20 hours. The product was filtered and washedwith 1 mL of CH₃CN. 375 mg of Tiotropium was obtained (HPLC purity92.21%, starting material 7.68%).

Example 15 Preparation of Tiotropium Bromide

0.52 g of N-demethyl tiotropium (1.39 mmol) was suspended in a flaskunder nitrogen with 5.23 g of CH₃CN. 1.35 g of CH₃Br 50% w/w solution inCH₃CN (0.0071 mol) was loaded, and the suspension was left understirring at 22° C. for 12 hours. The product was filtered and washedwith 1 mL of CH₃CN. 572 mg of wet Tiotropium was obtained (HPLC purity99.89%, starting material 0.07%).

Example 16 Preparation of Tiotropium Bromide

4.96 g of N-demethyl tiotropium (13.2 mmol) were loaded in a flask undernitrogen with 49.6 mL of CH₃CN. A suspension was obtained. 12.61 g ofCH₃Br 50% w/w —CH₃CN solution- (0.066 mol) were loaded. The suspensionwas left under stirring at 22° C. for 64 hours. The product was filteredand washed with 2 mL of CH₃CN. 6.93 g of wet Tiotropium was obtained,and dried under vacuum at 45° C. for 22 h (residual pressure 4 mbar).5.9 g of dry product (purity 99.8%, start 0.107%) was obtained.

Example 17 Crystallization of Tiotropium bromide

Crude Tiotropium bromide (1.00 g) was dissolved in absolute ethanol (65mL) at 78° C. The solution was heated to 78° C. for about 30 min, andthen was cooled to 22° C. in at least 6 hours. The obtained suspensionwas maintained at 22° C. for at least 3 hours, and then was filtered ona sintered glass funnel, and the solid was washed twice with absoluteethanol (2×1.0 mL). The solid was dried for 30 min. at 22° C. under N₂flow, and then for 9 hours at 60° C. under reduced pressure (17 mbar).0.66 g of Tiotropium bromide was obtained.

Example 18 Preparation of Tiotropium Bromide Monohydrate from TiotropiumBromide Ethanolate

13.45 g of dry Tiotropium bromide from example 16 was suspended in 80.7mL of water and the suspension was stirred at room temperature for 4 h.After it was filtered washing with 10 mL of water was conducted. Theproduct was left on the filter under vacuum and under nitrogen at roomtemperature for 15 min. 11.66 g of monohydrate was obtained. The contentof water on the sample was 4.3% (TGA analysis).

Example 19 Comparative Preparation of Tiotropium Bromide from N-demethylTiotropium According to U.S. Pat. No. 5,610,163

10.0 g (0.0265 mole) of scopine di-(2-thienyl)glycolate was dissolved ina mixture comprising 20 mL of anhydrous methylene chloride and 30 mL ofanhydrous acetonitrile and treated with 12.8 g (0.1325 mole) of methylbromide (as 50% strength solution in anhydrous acetonitrile), and thereaction mixture was allowed to stand for 24 hours at room temperaturein a tightly sealed reaction vessel. Crystals were precipitated duringthis time. They are filtered off under suction, washed using methylenechloride and dried at 35° C.-under reduced pressure. White crystals wereobtained (from methanol/acetone), m.p. 217.8 C. (decomposition) afterdrying at 111° C. under reduced pressure.

Example 20 Preparation of Scopine Hydrochloride in Absolute Ethanol (5vol) with Precipitation in HCl 37%

10.0 g (22.84 mmol) of scopolamine hydrobromide trihydrate was suspendedin 50 mL of absolute ethanol, and cooled to 0° C. Sodium borohydride(3.46 g, 68.6 mmol) was then added portion-wise while maintaining thetemperature at a maximum of 30° C.

4.8 mL of water was then added to the reaction mixture, and after 30minutes the suspension was filtered on decalite pad, and washed with 10mL of absolute ethanol.

The solution was then cooled to 0° C., and acidified with hydrochloricacid 37% in water to obtain a pH of 1.

100 mL of tetrahydrofuran was added drop-wise to the reaction mixture at0° C., and it was maintained at 0° C. for 8 hours

The white solid was filtered on Goch P3, and dried at 50° C. undervacuum for 16 hours, yielding 12.8 g (52%).

Example 21 Preparation of N-Demethyl-Tiotropium

13.2 g (0.064 mol) of scopine hydrochloride was suspended in 165 mL ofdimethylformamide at 25° C., then 17.6 g (0.127 mol) of anhydrouspotassium carbonate were added, and the mixture was stirred at roomtemperature for about 60 minutes. 16.2 g (0.064 mol) of methyldi-(2-thienyl)glycolate was dissolved in 30 mL of dimethylformamide, andwith 4.4 g 0.032 mol) of anhydrous potassium carbonate, they were addedto the reaction mixture at about 60-65° C. The suspension was heated to65° C., under vacuum (70-100 mbar), and under nitrogen stripped (2.2-2.4L/min) for 18 hours.

At the end of the reaction, the distilled DMF was re-introduced to thereaction mixture and the other 2 volumes of DMF, for a total of 15volumes (225 mL), were added. The reaction mixture was cooled to 0° C.,and acidified to a pH of 3 with about 168 mL of 2M HBr (temperatureduring addition was below 20° C.). The obtained solution was extractedtwice with 85 mL of toluene, and the combined aqueous phases were thencooled to 0-5° C., and basified with 8.5 g of solid potassium carbonateto a pH of 9. After one hour at 0° C., the solid was filtered on GochP3, and washed five times with 60 mL of water to obtain a pH of 7. Thesolid was dried under vacuum at 45° C. for 16 hours yielding 16.5 g (69%yield, 98.3% HPLC purity).

1. A process for the preparation of N-demethyl-tiotropium of formulaIII,

comprising a) combining methyl-di-(2-thienyl)-glycolate of formula I,

with a scopine base, a weak organic base and a polar organic solvent toform a mixture; and b) heating the mixture; wherein the weak organicbase is selected from K₂CO₃, NaHCO₃, Na₂CO₃, and Cs₂CO₃.
 2. The processof claim 1, wherein the weak organic base is used in an amount fromabout 1 to about 1.5 mole equivalents of the weak organic base per moleequivalent of the scopine base.